NSF Nanoscale Science and Engineering Grantees Conference, Dec 3-6, 2007
Grant # : BES0608934
NIRT: Active Nanostructure Enabled On-Chip Spectroscopy System for
Cancer Detection
NSF NIRT Grant BES0608934
PIs: Won
J.-B. Lee2, Lynne Bemis3 and Bill Robinson3
1
Department of Electrical & Computer Engineering, University of Colorado at Boulder
2
Department of Electrical Engineering, University of Texas at Dallas
3
School of Medicine, University of Colorado at Denver and Health Sciences Center
Park1,
The ultimate goal of this project is to develop an on-chip spectroscopy system for cancer
detection. The on-chip spectrometer consists of a tunable negative index lens, light source,
photodetector and a microfluidic channel through which blood sample containing nanoprobes
will be passed. The research activities are thus comprised of three different phases: development
of tunable negative index lens, system integration and nanoprobes for gene detection.
Negative Index Photonic Crystal: Negative refraction is the key phenomenon to be used for
both light collection and frequency selection in the proposed on-chip spectroscopy system. We
propose to develop negative index lens based on photonic crystal (PC) structure. There are two
distinct mechanisms through which PCs may exhibit negative refraction. One is through the
second photonic band which exhibits negative slope in its dispersion diagram and the other is
when the photonic crystal has giant anisotropy. We have experimentally demonstrated the
lensing effect in the near-infrared region in both cases [1,2]. The PC structures were fabricated
on a silicon-on-insulator (SOI) substrate by etching periodic array of holes along with input and
output waveguides. Fig. 1(a) shows the PC structure for negative index imaging through the
second photonic band. Fig 1(b) shows the far-field infrared image in which the bright spot after
the PC indicates focusing. Furthermore, the inset shows the light output from the output
waveguide array in which only the central waveguide is strongly illuminated. Fig 1(c) is another
Si PC structure designed to exhibit negative refraction due to large anisotropy. The color pattern
is the near-field image overlaid on top of scanning electron micrograph. The intense spot just
inside the PC region shows the internal focus due to negative refraction. We have also
investigated the phase front propagation in the PC and directly demonstrated the reversal of
phase front curvature due to the large anisotropy. It was the first direct observation of phase front
propagation in a PC structure.
(a)
(b)
(c)
Input
Waveguide
Output
NIM PC
Fig. 1 (a) Scanning electron micrograph (SEM) of a negative index PC lens co-fabricated with
input and output waveguides. (b) Far-field infrared image showing focusing due to negative
index PC (Inset: Infrared image of output waveguide array in which only one waveguide is
strongly illuminated.) (c) Near-field scanning optical micrograph image overlaid on top of an
SEM micrograph of a Si PC exhibiting negative refraction due to large anisotropy.
NSF Nanoscale Science and Engineering Grantees Conference, Dec 3-6, 2007
Grant # : BES0608934
Tuning the negative index imaging will be accomplished by adopting the mechanically tunable
PC concept [3]. It takes advantage of the fact that the optical properties of a PC is strongly
dependent on the structural design and symmetry and thus achieves wide tunability by exerting
mechanical force to modify structural parameters.
Microfluidic Channel and System Integration: Heterogeneous integration of light source,
photodetector and microfluidic channel with the negative index lens is critical for compact,
integrated on-chip spectroscopy system. We designed and fabricated microfluidic channels for
droplet manipulation technology. We have demonstrated the droplet manipulation test structure
as shown in Fig. 2. Initial structures suffered electrolysis damage after a few cycles of
operations. This problem was solved by using both high quality and thinner insulating layer
along with a combination of optimal surface coatings. With these improvements, operational
voltage has been substantially lowered (by a factor of 2) and the electrolysis is no longer a
problem. Up to this point, the droplet manipulation was demonstrated with water. The next
logical step would be testing of the droplet manipulation for blood samples or blood-like liquids
to be ready for the monitoring of the cancer specific DNA-hybridized blood samples.
(a)
(b)
Fig. 2 (a) SEM image of lithographically fabricated SU-8 microfluidic channel (b) Schematic
diagrams for the droplet manipulation test structures.
In the area of system integration, a tunable photonic crystal structure was fabricated and
integrated with micro-heater, as shown in Fig. 3. The Si-based PC was designed to select
transverse-magnetic (TM) polarization, acting as a polarizer. The PC fabrication was done by
focused ion beam (FIB) and reactive ion etch (RIE) while the micro heater was fabricated using
UV lithography technique. Alignment between the nano-patterned structures with the UV
lithography, which is a critical task in the proposed system integration has been successfully
achieved. Also, vertical cavity surface emitting laser has been successfully integrated by the
heterogeneous integration process. A similar process will be used for photodetector too.
(a)
Output waveguide
Input waveguide
4.9 μm
(b)
TM polarizer
Fig. 3 (a) Micro heater integrated photonic crystal light modulator. (b) Heterogeneously
integrated vertical cavity surface emitting laser.
NSF Nanoscale Science and Engineering Grantees Conference, Dec 3-6, 2007
Grant # : BES0608934
Nanoprobes for DNA detection: Malignant melanoma is the most rapidly increasing cancer
throughout the world. Current methods for detection of metastatic malignant melanoma are not
adequate. At least 20% of patients develop advanced disease, which is rarely curable. In this
proposal we are applying the use of nanoparticles for cancer detection. We specifically target
BRAF, one of the most commonly mutated genes in melanoma. BRAF is mutated in as many as
70% of melanoma cases. Detection of BRAF mutations is thus necessary for determining which
patients will respond to therapeutics targeting melanoma cells that harbor BRAF mutations.
We synthesized gold nanoparticles, nanoshells and nanorods by the solution-based techniques.
The synthesized nanomaterials exhibited well-defined sizes and their optical extinction spectra
were in excellent agreement with the Mie theory. They are then conjugated with oligonucleotides
targeting mutated BRAF. The conjugated nanoparticles maintained the strong plasmon
resonance, which is optically detected and monitored in the subsequent hybridization process.
We then conducted hybridization experiments with 49 base-long single stranded primers which
are exactly complementary to the primers attached to the gold nanoprobes. As the primers
hybridize with one another, the gold particles begin to agglomerate, resulting in a peak shift in
the optical spectrum, as shown in Fig. 4(a). This work is currently being extended to longer,
double-stranded targets, which resemble more closely the actual genes in patient samples.
(a)
2.5
Before hybridization
After hybridization
2
0.6
0.5
(b)
0.4
1.5
0.3
1
0.2
0.5
0.1
923
888
852
815
777
738
699
660
619
579
537
495
453
0
410
0
Fig. 4 (a) Optical extinction spectra taken before and after the hybridization experiments with the
49-bases long target strands. (b) Optical micrograph of melanoma cells treated with BRAF
mutant specific nanoprobes, which are seen as bright spots inside the cells.
It would be helpful in the clinic if we could use the nanoparticle approach to identify which cells
in a given tumor sample actually harbor the BRAF point mutation. For this, we initially used
cells known to harbor specific alterations in BRAF and queried with nanoprobes. At the single
particle direct labeling we could not identify those cells with a mutation. However, when we
added a second round of nanoparticles that would bind in multiple places to the first probe we
were able to clearly see hybridization in the mutant cells with the mutant specific nanoprobe and
not with the normal BRAF nanoprobes as shown in Fig. 4(b). The detection of BRAF genes in
both blood samples and cells will be further optimized and eventually used in the on-chip
spectroscopy system.
References
[] E. Schonbrun, T. Yamashita, W. Park and C. J. Summers, “Negative Index Imaging by an Index-Matched
Photonic Crystal Slab”, Phys. Rev. B 73, 195117 (2006)
[2] E. Schonbrun, Q. Wu, W. Park, M. Abashin, Y. Fainman, T. Yamashita and C. J. Summers, “Wavefront
Evolution of Negatively Refracted Waves in Photonic Crystals”, Appl. Phys. Lett. 90, 041113 (2007)
[3] W. Park and J.-B. Lee, “Mechanically tunable photonic crystal structures”, Appl. Phys. Lett., 85, 4845 (2004)